Biology Reference
In-Depth Information
Hz delivered in vivo over a series of 11 days induced sprouting in the hippocampal CA3 and
intermolecular layer [48]. In addition, the study reported that mossy fiber sprouting induced
by LTP trains can occur in the absence of neurodegeneration.
In another study by Hassan et al., 200 Hz in vivo stimulation was applied over a period of
10 days to the angular bundles of the dentate gyrus in rats [49]. These results confirmed the
Adams study and demonstrated that both morphological and functional changes to the
hippocampus, similar to what is seen after kindling stimulation, can also occur with LTP
protocols used for long-lasting synaptic plasticity, but is not associated with seizure activity.
In another study by Escobar et al. [50] using male rats, it was found that 100 Hz
stimulation (two 1 sec trains with intertrain interval of 20 secs) in vivo to the mossy fiber
pathway (mossy fiber-CA3 synapse) resulted in bilateral synaptogenesis. In this study,
animals showing any seizure activity were eliminated from the results. In agreement with past
studies, the effect was NMDA-independent since the NMDA antagonist (
+)
CPP did not
prevent LTP in this pathway.
In addition, Tim Teyler et al. have proposed a very intriguing hypothesis that may
provide a partial explanation for LTP-induced mossy fiber sprouting. In a past landmark study
Dr. Teyler made an important distinction between NMDA forms of LTP and voltage-
dependent calcium channel (VDCC) forms of LTP where he and his student Larry Grover
showed that some forms of LTP could be induced in the CA1 hippocampus without the
involvement of the NMDA receptor [51]. More recently he has also suggested that activity in
a primary epileptic focus is of sufficient magnitude to drive efferents from the primary focus
at rates that will result in the induction of VDCC forms of LTP [8]. The hypothesis advocates
that VDCC-LTP can be involved in epileptic processes even though the mechanism is also a
normal component of synaptic plasticity. He further hypothesized that the synaptic
enhancement mediated by VDCC-LTP leads to the activation of neurotrophins and the
sprouting of aberrant connections in a secondary focus, thus hinting at the possibility that
VDCC blockers might be beneficial at preventing the establishment of secondary epileptic
foci.
Gene expression profiling
A review of past work identifies several important relationships between epileptic
neuropathology and plasticity that are under investigation [7]. One particularly interesting
area is the expression of neurotrophic factors in mossy fiber sprouting and/or during seizure
activity. Studies suggest that many forms of activity-dependent changes (including LTP and
ictal episodes) upregulate growth factor mRNA, transcription factors, and gene expression in
the dentate and therefore function as processes that drive mossy fiber sprouting, which are
dependent on the level of neural activity [7]. To this end, our laboratory is currently using
DNA microarrays or “gene chips” in order to assess the potential up-regulation or
downregulation of specific genes associated with various neurotrophic factors and in
association with the activation of specific transcription factors, in experimental paradigms of
LTP and epilepsy.
A DNA microarray is a collection of microscopic DNA sites on a grid, commonly
representing single genes, arrayed on a solid surface by attachment to a chemical matrix.
